Severe obesity affects over 15 million U.S. adults and is a well-established risk factor for developing some types of cancer. In 2007, obesity was responsible for approximately 50,500 new cases of cancer in women and 34,000 new cases in men. Obesity is a considered a well-established risk factor for several types of cancer. However, clinical trials to specifically examine whether intentional weight loss reduces cancer risk have not been done and data from observational studies is sparse and less convincing. Currently, bariatric surgery is the only proven treatment for sustained weight loss in the severely obese patient and is accompanied by immediate alterations of metabolic processes that may also influence cancer growth. Recent observational studies have suggested that bariatric surgery can decrease the incidence of cancer but have either used outdated procedures or have not been adequately controlled. Research is needed to establish whether intentional weight loss can reduce cancer risk to help motivate and guide future research and policy decisions regarding implementation of weight management programs in the US. The goals of this project are 1) estimate the impact of bariatric surgery versus non-surgical treatment on the incidence of cancer (all types) in severely obese patients, 2) explore whether the reduction in risk of cancer after surgery is mediated by weight loss, and 3) determine which patient characteristics are most strongly associated with a reduction in cancer incidence in severely obese patients. This study will utilize data from electronic administrative, medical record databases, and cancer registries from five large, integrated health plans and care delivery systems in the HMO Research Network (HMORN) to estimate the long-term impact of bariatric surgery on cancer outcomes among severely obese patients. We will estimate the incidence of cancer among severely obese (BMI e35) patients who underwent bariatric surgery of any type from 2005-2012 compared to severely obese patients who did not undergo bariatric surgery during the same time period. Main comparisons will use a control population matched by both the propensity for bariatric surgery and the propensity for developing incident cancer. Additional analyses will explore the impact of bariatric surgery on the incidence of cancer (all types and obesity specific types) in severely obese women and the heterogeneity of treatment effects by age, race/ethnicity, and bariatric surgery type. The proposed research will determine whether significant weight loss can reduce cancer incidence using the latest advances in comparative effectiveness research. We will be able to provide insight into potential mechanisms of reducing cancer incidence following surgery by identifying whether the change in risk is mediated by weight loss.